WO2019000682A1 - Rho相关蛋白激酶抑制剂、包含其的药物组合物及其制备方法和用途 - Google Patents

Rho相关蛋白激酶抑制剂、包含其的药物组合物及其制备方法和用途 Download PDF

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Publication number
WO2019000682A1
WO2019000682A1 PCT/CN2017/104290 CN2017104290W WO2019000682A1 WO 2019000682 A1 WO2019000682 A1 WO 2019000682A1 CN 2017104290 W CN2017104290 W CN 2017104290W WO 2019000682 A1 WO2019000682 A1 WO 2019000682A1
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WIPO (PCT)
Prior art keywords
compound
ring
mmol
group
reaction
Prior art date
Application number
PCT/CN2017/104290
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English (en)
French (fr)
Chinese (zh)
Inventor
赵焰平
王红军
李功
姜媛媛
李想
周丽莹
刘亚男
Original Assignee
北京泰德制药股份有限公司
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Application filed by 北京泰德制药股份有限公司 filed Critical 北京泰德制药股份有限公司
Priority to KR1020197037714A priority Critical patent/KR102563325B1/ko
Priority to CN201780090148.0A priority patent/CN110573501B/zh
Priority to JP2019572785A priority patent/JP2020525525A/ja
Priority to CA3063616A priority patent/CA3063616A1/en
Priority to CN202311291547.7A priority patent/CN117343049A/zh
Priority to CN201880028332.7A priority patent/CN110582489B/zh
Priority to US16/344,965 priority patent/US11390609B2/en
Priority to EP18824200.2A priority patent/EP3647311B1/en
Priority to KR1020197038757A priority patent/KR102585860B1/ko
Priority to AU2018294054A priority patent/AU2018294054B2/en
Priority to PCT/CN2018/093713 priority patent/WO2019001572A1/zh
Priority to ES18824200T priority patent/ES2969536T3/es
Priority to CN202010118186.6A priority patent/CN111217797B/zh
Priority to JP2019572768A priority patent/JP7311228B2/ja
Publication of WO2019000682A1 publication Critical patent/WO2019000682A1/zh
Priority to US17/367,726 priority patent/US20230030115A1/en
Priority to AU2022221446A priority patent/AU2022221446B2/en
Priority to JP2023110247A priority patent/JP2023126907A/ja

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    • C—CHEMISTRY; METALLURGY
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    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems
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    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
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    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
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    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
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    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
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    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom

Definitions

  • the present invention relates to a Rho-associated protein kinase inhibitor, a pharmaceutical composition comprising the same, a process for the preparation thereof, and use thereof for preventing or treating a Rho-associated protein kinase (ROCK) mediated disease.
  • a Rho-associated protein kinase inhibitor a pharmaceutical composition comprising the same, a process for the preparation thereof, and use thereof for preventing or treating a Rho-associated protein kinase (ROCK) mediated disease.
  • ROCK Rho-associated protein kinase
  • Rho-associated protein kinase is a serine/threonine protein kinase of the AGC kinase family, which includes two subtypes, ROCK1 and ROCK2.
  • ROCK1 and ROCK2 are differentially expressed and regulated in specific tissues.
  • ROCK1 is ubiquitously expressed at relatively high levels, while ROCK2 is preferentially expressed in heart, brain and skeletal muscle.
  • ROCK is the first Rho protein downstream effector to be discovered by phosphorylating downstream effector proteins (MLC, Lin-11, Isl-1, LIMK, ERM, MARCKS, CRMP-2, etc.) to achieve its biological functions.
  • MLC phosphorylating downstream effector proteins
  • Fasudil is currently approved as a ROCK inhibitor in Japan for the treatment of cerebral vasospasm and ischemia.
  • small-molecule ROCK inhibitors most of them are topical ophthalmic drugs, and there are currently no small-molecule ROCK inhibitors suitable for systemic administration.
  • the present invention provides a compound for use as an inhibitor of ROCK (preferably ROCK2) which has excellent inhibitory activity against ROCK (preferably ROCK2), good selectivity (relative to ROCK1, higher selectivity to ROCK2), and better Physicochemical properties (eg solubility, physical and/or chemical stability), improved pharmacokinetic properties (eg improved bioavailability, suitable half-life and duration of action), improved safety (lower toxicity) And/or fewer side effects, wider treatment window) and other superior properties.
  • ROCK preferably ROCK2
  • One aspect of the invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, wherein Said compound has the structure of formula (I):
  • Ring D is absent or is selected from a saturated or partially unsaturated C 3-10 hydrocarbon ring, a saturated or partially unsaturated 3-10 membered heterocyclic ring, a C 6-10 aromatic ring and a 5-14 membered heteroaryl ring.
  • Ring E is selected from
  • R 1 and R 10 When one of R 1 and R 10 is H and the other is When ring C is not a 5-membered heteroaryl ring; when both R 1 and R 10 are H, ring A contains at least 1 nitrogen atom and is not a 5 or 6 membered ring; when one of R 1 and R 10 is H and The other is Ring C is not a 5-membered heteroaryl ring; and when one of R 1 and R 10 is H and the other is H or acetyl, ring D is absent;
  • R 5 and R 6 are each independently selected from H, C 1-6 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, 5-14, each occurrence. a heteroaryl group and a C 6-12 aralkyl group;
  • n is each independently an integer of 0, 1, 2 or 3 at each occurrence;
  • n is an integer of 0, 1, or 2;
  • i is an integer of 0, 1, or 2;
  • g is an integer of 0, 1, 2, 3 or 4.
  • compositions comprising a prophylactically or therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate thereof, N- An oxide, an isotopically labeled compound, a metabolite or prodrug, and one or more pharmaceutically acceptable carriers, preferably a solid formulation, a semisolid formulation, a liquid formulation or a gaseous formulation.
  • Another aspect of the invention provides a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or Use of a medicament or a pharmaceutical composition of the invention in the manufacture of a medicament for use as a Rho-related protein kinase (ROCK) inhibitor, preferably a selective ROCK2 inhibitor.
  • a Rho-related protein kinase (ROCK) inhibitor preferably a selective ROCK2 inhibitor.
  • Another aspect of the invention provides a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or A pharmaceutical or pharmaceutical composition of the invention for use as a Rho-related protein kinase (ROCK) inhibitor, preferably a selective ROCK2 inhibitor.
  • ROCK Rho-related protein kinase
  • Another aspect of the invention provides a method of preventing or treating a Rho-associated protein kinase (ROCK) mediated disease, the method comprising administering to an individual in need thereof an effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof , esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs or pharmaceutical compositions of the invention.
  • a Rho-associated protein kinase (ROCK) mediated disease comprising administering to an individual in need thereof an effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof , esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs or pharmaceutical compositions of the invention.
  • ROCK Rho-associated protein kinase
  • Another aspect of the invention provides a method of preparing a compound of the invention.
  • alkylene denotes a saturated divalent hydrocarbon group, preferably a saturated divalent hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms, such as methylene, ethylene, Propylene or butylene.
  • alkyl is defined as a linear or branched saturated aliphatic hydrocarbon.
  • an alkyl group has from 1 to 12, such as from 1 to 6 carbon atoms.
  • C1-6 alkyl refers to a linear or branched group of 1 to 6 carbon atoms (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl) Base, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or n-hexyl), optionally substituted by one or more (such as 1 to 3) suitable substituents Substituted by halogen (in this case the group is referred to as "haloalkyl”) (eg CH 2 F, CHF 2 , CF 3 , CCl 3 , C 2 F 5 , C 2 Cl
  • C 1-4 alkyl refers to a linear or branched aliphatic hydrocarbon chain of 1 to 4 carbon atoms (ie methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, Sec-butyl or tert-butyl).
  • alkenyl refers to a linear or branched monovalent hydrocarbon radical comprising one double bond and having 2 to 6 carbon atoms (“C 2-6 alkenyl”).
  • the alkenyl group is, for example, a vinyl group, a 1-propenyl group, a 2-propenyl group, a 2-butenyl group, a 3-butenyl group, a 2-pentenyl group, a 3-pentenyl group, a 4-pentenyl group, and 2 Hexyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl and 4-methyl-3-pentenyl.
  • the compounds of the invention may exist in pure E (enthafen) form, pure Z (zusammen) form, or any mixture thereof.
  • alkynyl refers to a monovalent hydrocarbon radical containing one or more triple bonds, which preferably has 2, 3, 4, 5 or 6 carbon atoms, such as ethynyl or propynyl.
  • cycloalkyl refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (eg, a monocyclic ring such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl).
  • cyclooctyl cyclodecyl, or bicyclic, including spiro, fused or bridged systems (such as bicyclo [1.1.1] pentyl, bicyclo [2.2.1] heptyl, bicyclo [3.2.1] octyl Or bicyclo [5.2.0] anthracenyl, decahydronaphthyl, etc.)), which is optionally substituted by one or more (such as 1 to 3) suitable substituents.
  • the cycloalkyl group has 3 to 15 carbon atoms.
  • C 3-6 cycloalkyl refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring of 3 to 6 ring-forming carbon atoms (eg, cyclopropyl, cyclobutyl, cyclopentyl or ring). Hexyl), which is optionally substituted with one or more (such as 1 to 3) suitable substituents, such as methyl substituted cyclopropyl.
  • cycloalkylene means, for example, from 3 to 10 (suitably from 3 to 8, more suitably from 3 to 6) ring carbons.
  • Atomic saturation ie, “cycloalkylene” and “cycloalkyl”
  • unsaturated ie, having one or more double and/or triple bonds in the ring
  • a monocyclic or polycyclic hydrocarbon ring Including but not limited to (sub)cyclopropyl (cyclo), (sub)cyclobutyl (cyclo), (sub)cyclopentyl (cyclo), (sub)cyclohexyl (cyclo), (sub)cycloheptyl ( Ring), (sub)cyclooctyl (ring), (sub)cyclodecyl (ring), (sub)cyclohexenyl (ring), and the like.
  • heterocyclyl As used herein, the terms “heterocyclyl”, “heterocyclylene” and “heterocycle” mean, for example, from 3 to 10 (suitably from 3 to 8, more suitably from 3 to 6) a ring atom, wherein at least one of the ring atoms is a hetero atom selected from N, O and S and the remaining ring atoms are saturated (ie heterocycloalkyl) or partially unsaturated (ie one or more within the ring) Double bond and/or triple bond) cyclic group.
  • 3-10 membered (sub)heterocyclic (yl) has 2 to 9 (eg, 2, 3, 4, 5, 6, 7, 8 or 9) ring carbon atoms and is independently selected from N a saturated or partially unsaturated (sub)heterocyclic ring of one or more (e.g., 1, 2, 3 or 4) heteroatoms of O and S.
  • heterocyclylene group and the heterocyclic ring group include, but are not limited to, (meth)oxiranyl, (i)aziridine, (a) azetidinyl, (sub)oxy Oxetanyl, (i)tetrahydrofuranyl, (di)dioxolinyl, (i)pyrrolidinyl, (i)pyrrolidone, (im)imidazolidinyl, (Asia) Pyrazolyl, (i)pyrroline, (i)tetrahydropyranyl, (i)piperidinyl, (y)morpholinyl, (di)dithianyl, (sub) Thimorpholinyl, (i)piperazinyl or (tri)trithianyl.
  • the group also encompasses bicyclic systems, including spiro, fused or bridged systems (such as 8-azaspiro[4.5]decane, 3,9-diazaspiro[5.5]undecane, 2-nitrogen Heterobicyclo[2.2.2]octane, etc.).
  • Heterocyclylene and heterocycle may be optionally substituted with one or more (e.g., 1, 2, 3 or 4) suitable substituents.
  • (sub)aryl and “aromatic ring” refer to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated pi-electron system.
  • C 6-10 (sub)aryl” and “C 6-10 aromatic ring” mean an aromatic group containing from 6 to 10 carbon atoms, such as (phenylene)phenyl. (Benzene ring) or (methylene) naphthyl (naphthalene ring).
  • the (sub)aryl and aromatic rings are optionally substituted by one or more (such as 1 to 3) suitable substituents (e.g., halogen, -OH, -CN, -NO 2 , C 1-6 alkyl, etc.) .
  • suitable substituents e.g., halogen, -OH, -CN, -NO 2 , C 1-6 alkyl, etc.
  • heteroaryl and “heteroaryl” refer to a monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 1 or 2 or 3 or 4 or 5 or 6 or 9 or 10 carbon atoms, and which comprise at least one hetero atom which may be the same or different (the hetero atom is, for example, oxygen, nitrogen) Or sulfur), and, in each case, may be benzo-fused.
  • “(sub)heteroaryl” or “heteroaryl” is selected from (i)thienyl, (i)furanyl, (i)pyrrolyl, (i)oxazolyl, (sub)thiazolyl, (i)imidazolyl, (i)pyrazolyl, (i)isoxazolyl, (i)isothiazolyl, (sub)oxadiazolyl, (sub)triazolyl, (sub)thiadiazolyl And their benzo derivatives; or (i)pyridyl, (pyridazinyl), (i)pyrimidinyl, (i)pyrazinyl, (i)triazinyl, etc., and their benzo derivative.
  • aralkyl as used herein preferably denotes an aryl or heteroaryl substituted alkyl group, wherein the aryl, heteroaryl and alkyl are as defined herein.
  • the aryl group can have from 6 to 14 carbon atoms
  • the heteroaryl group can have from 5 to 14 ring atoms
  • the alkyl group can have from 1 to 6 carbon atoms.
  • Exemplary aralkyl groups include, but are not limited to, benzyl, phenylethyl, phenylpropyl, phenylbutyl.
  • halo or halogen group, as used herein, is defined to include F, Cl, Br or I.
  • substituted means that one or more (eg, one, two, three or four) hydrogens on the designated atom are replaced by the selection of the indicated group, provided that the specified atom is not present at present.
  • the normal valence in the case and the substitution form a stable compound. Combinations of substituents and/or variables are permissible only if such combinations form stable compounds.
  • substituent may be unsubstituted or (2) substituted. If the carbon of the substituent is described as being optionally substituted by one or more of the list of substituents, then one or more hydrogens on the carbon (to the extent of any hydrogen present) may be independently and/or together independently The optional substituents selected are substituted. If the nitrogen of the substituent is described as being optionally substituted by one or more of the list of substituents, then one or more hydrogens on the nitrogen (to the extent of any hydrogen present) may each be independently selected. Substitute substitution.
  • each substituent is selected independently of the other.
  • each substituent may be the same or different from another (other) substituent.
  • one or more means 1 or more than 1, such as 2, 3, 4, 5 or 10 under reasonable conditions.
  • a point of attachment of a substituent may come from any suitable position of the substituent.
  • the invention also includes all pharmaceutically acceptable isotopically-labeled compounds which are identical to the compounds of the invention, except that one or more atoms are of the same atomic number but the atomic mass or mass number differs from the atomic mass prevailing in nature. Or atomic substitution of mass.
  • suitable contain a compound of the present invention isotopes include (but are not limited to) isotopes of hydrogen (e.g., deuterium (2 H), tritium (3 H)); isotopes of carbon (e.g.
  • Chlorine isotope eg 36 Cl
  • fluorine isotopes eg 18 F
  • iodine isotopes eg 123 I and 125 I
  • nitrogen isotopes eg 13 N and 15 N
  • oxygen isotopes eg 15 O
  • phosphorus isotope eg 32 P
  • sulfur isotope eg 35 S
  • Certain isotopically-labeled compounds of the invention e.g., those incorporating radioisotopes
  • are useful in drug and/or substrate tissue distribution studies e.g., assays).
  • the radioisotope ruthenium (i.e., 3 H) and carbon-14 (i.e., 14 C) are particularly useful for this purpose because of their ease of incorporation and ease of detection.
  • Substitution with positron emitting isotopes eg, 11 C, 18 F, 15 O, and 13 N
  • PET positron emission tomography
  • Isotopically labeled compounds of the invention can be prepared by replacing the previously employed non-labeled reagents with suitable isotopically labeled reagents by methods analogous to those described in the accompanying routes and/or examples and preparations.
  • the pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent can be substituted with an isotope, for example, D 2 O, acetone-d 6 or DMSO-d 6 .
  • stereoisomer denotes an isomer formed by at least one asymmetric center.
  • a compound having one or more (eg, one, two, three or four) asymmetric centers it can produce a racemic mixture, a single enantiomer, a mixture of diastereomers, and Diastereomers.
  • Specific individual molecules can also exist as geometric isomers (cis/trans).
  • this hair The compounds of the present invention may exist as a mixture of two or more structurally different forms (generally referred to as tautomers) in a rapidly equilibrating manner.
  • tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers Wait. It is to be understood that the scope of the present application covers all such ratios in any ratio (eg, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99). %) isomer or a mixture thereof.
  • Solid lines can be used in this article Solid wedge Virtual wedge
  • the carbon-carbon bonds of the compounds of the invention are depicted.
  • the use of solid lines to delineate linkages bonded to an asymmetric carbon atom is intended to include all possible stereoisomers at the carbon atom (eg, specific enantiomers, racemic mixtures, etc.).
  • the use of a solid or virtual wedge to characterize a bond to an asymmetric carbon atom is intended to indicate the presence of the stereoisomers shown.
  • solid and virtual wedges are used to define relative stereochemistry rather than absolute stereochemistry.
  • the compounds of the invention are intended to be stereoisomers (including cis and trans isomers, optical isomers (eg, R and S enantiomers), diastereomers, Geometric isomers, rotamers, conformers, atropisomers, and mixtures thereof exist.
  • the compounds of the invention may exhibit more than one type of isomerism and consist of a mixture thereof (e.g., a racemic mixture and a diastereomeric pair).
  • the invention encompasses all possible crystalline forms or polymorphs of the compounds of the invention, which may be a single polymorph or a mixture of more than one polymorph in any ratio.
  • compositions of the invention may exist in free form for treatment or, where appropriate, in the form of their pharmaceutically acceptable derivatives.
  • pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, N-oxides, metabolites or prodrugs, which are administered to a patient in need thereof
  • the compound of the invention, or a metabolite or residue thereof, can be provided directly or indirectly after the drug.
  • a “compound of the invention” it is also intended to encompass the various derivative forms described above for the compound.
  • the pharmaceutically acceptable salts of the compounds of the present invention include the acid addition salts and base addition salts thereof.
  • Suitable acid addition salts are formed from acids which form pharmaceutically acceptable salts. Examples include acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, hydrogen sulfate/sulfate, borate, camphorsulfonate , citrate, cyclamate, ethanedisulfonate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate Salt, sea benzoate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleic acid Salt, malonate, methanesulfonate, methyl sulfate, naphthylate, 2-naphthalene sulfonate, nicotinate, nitrate, orotate, oxalate, palmitic acid
  • Suitable base addition salts are formed from bases which form pharmaceutically acceptable salts. Examples include aluminum salts, arginine salts, benzathine penicillin salts, calcium salts, choline salts, diethylamine salts, diethanolamine salts, glycinates, lysine salts, magnesium salts, meglumine salts, ethanolamine salts, Potassium salt, sodium salt, tromethamine salt and zinc salt.
  • esters means an ester derived from a compound of the formulae herein, which includes a physiologically hydrolyzable ester (which can be hydrolyzed under physiological conditions to release the free acid or alcohol form of the invention). Compound).
  • the compounds of the invention may also be esters per se.
  • the compound of the present invention may exist in the form of a solvate (preferably a hydrate) wherein the compound of the present invention contains a polar solvent as a structural element of the crystal lattice of the compound, particularly such as water, methanol or ethanol.
  • a polar solvent as a structural element of the crystal lattice of the compound, particularly such as water, methanol or ethanol.
  • the amount of polar solvent, particularly water, may be present in stoichiometric or non-stoichiometric ratios.
  • N-oxides are capable of forming N-oxides because nitrogen requires the use of a lone pair of electrons to oxidize to oxides; those skilled in the art will recognize that N-oxides can be formed.
  • Nitrogen-containing heterocycle Those skilled in the art will also recognize that tertiary amines are capable of forming N-oxides.
  • the synthesis of N-oxides for the preparation of heterocyclic and tertiary amines is well known to those skilled in the art and includes the use of peroxyacids such as peroxyacetic acid and m-chloroperoxybenzoic acid (MCPBA), hydrogen peroxide, alkyl groups.
  • MCPBA m-chloroperoxybenzoic acid
  • Hydrogen peroxide such as t-butyl hydroperoxide, sodium perborate and dioxirane such as dimethyl dioxirane oxidize heterocyclic and tertiary amines.
  • metabolites of the compounds of the invention i.e., substances formed in vivo upon administration of a compound of the invention. Such products may be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, and the like of the administered compound. Accordingly, the invention includes metabolites of the compounds of the invention, including by contacting a compound of the invention with a mammal A compound prepared by a method of producing the time of its metabolite.
  • the invention further includes within its scope prodrugs of the compounds of the invention which are certain derivatives of the compounds of the invention which may themselves have less or no pharmacological activity, when administered to or into the body It can be converted to a compound of the invention having the desired activity by, for example, hydrolytic cleavage.
  • prodrugs will be functional group derivatives of the compounds which are readily converted in vivo to the desired therapeutically active compound. Additional information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems", Volume 14, ACS Symposium Series (T. Higuchi and V. Stella).
  • Prodrugs of the invention may, for example, be known by those skilled in the art as “pro-moiety” (e.g., “Design of Prodrugs", H. Bundgaard (Elsevier, 1985))" It is prepared in place of the appropriate functional groups present in the compounds of the invention.
  • the invention also encompasses compounds of the invention containing a protecting group.
  • a protecting group In any process for preparing a compound of the invention, it may be necessary and/or desirable to protect a sensitive group or reactive group on any of the molecules of interest, thereby forming a chemically protected form of the compound of the invention. This can be achieved by conventional protecting groups, such as those described in T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which is incorporated herein by reference.
  • the protecting group can be removed at a suitable subsequent stage using methods known in the art.
  • the invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof Wherein the compound has the structure of formula (I):
  • Ring D is absent or is selected from a saturated or partially unsaturated C 3-10 hydrocarbon ring, a saturated or partially unsaturated 3-10 membered heterocyclic ring, a C 6-10 aromatic ring and a 5-14 membered heteroaryl ring.
  • Ring E is selected from
  • Ring when one of R 1 and R 10 is H and the other is When ring C is not a 5-membered heteroaryl ring; when both R 1 and R 10 are H, ring A contains at least 1 nitrogen atom and is not a 5 or 6 membered ring; when one of R 1 and R 10 is H and The other is Ring C is not a 5-membered heteroaryl ring; and when one of R 1 and R 10 is H and the other is H or acetyl, ring D is absent;
  • R 5 and R 6 are each independently selected from H, C 1-6 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, 5-14, each occurrence. a heteroaryl group and a C 6-12 aralkyl group;
  • n is each independently an integer of 0, 1, 2 or 3 at each occurrence;
  • n is an integer of 0, 1, or 2;
  • i is an integer of 0, 1, or 2;
  • g is an integer of 0, 1, 2, 3 or 4.
  • the invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof
  • the invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof
  • the above group is connected to X by one of two positions marked with # or ##, and the other position is connected to R 1 ,
  • j 0, 1, 2, 3 or 4;
  • R 9 and R 10 are each independently selected from the group consisting of halogen, methyl, ethyl, propyl and -CH 2 CH 2 -N(CH 3 ) 2 .
  • the above group is bonded to X by one of two positions marked with # or ##, and the other position is bonded to R 1 , provided that the atom to which X is attached is not a nitrogen atom.
  • the invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof ,among them for More preferably More preferably it is
  • the above group is connected to Y by one of two positions marked by * or **, and the other position is connected to X,
  • k 0, 1, 2, 3 or 4;
  • R 7 and R 8 are each independently selected from the group consisting of F, Cl, Br, I, cyano, methyl, ethyl, propyl, methoxy, trifluoromethyl at each occurrence. , phenyl, -O-CH 2 CH 2 -N(CH 3 ) 2 and -CH 2 CH 2 -N(CH 3 ) 2 .
  • the invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof , where ring E is Preferred
  • each occurrence of R 3 and R 4 is independently selected from the group consisting of H, F, Cl, Br, I, methyl, ethyl, propyl, methoxy, -O-ethylene. -N(CH 3 ) 2 .
  • ring E is
  • the invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof
  • the invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof
  • R 1a and R 1b are each independently selected from the group consisting of H, methyl, -CF 3 , ethyl, -CH 2 CF 3 , n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl, -ethylene-O-methyl, -CH 2 CN, -CH 2 CH 2 CN, -CH 2 CH 2 OH, Or R 1a and R 1b together with the atoms to which they are attached form the following groups:
  • the invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof Wherein the compound has any structure of the formula:
  • the present invention encompasses compounds obtained by any combination of the various embodiments.
  • the invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof , wherein the structure and characterization data of the compound are as follows:
  • the invention provides a method of preparing a compound of formula (II), comprising the steps of:
  • R 2 is H
  • Hal 1 and Hal 2 are the same or different halogens, such as F, Cl, Br or I;
  • PG 1 is a carboxy protecting group, preferably a C 1-6 alkyl group
  • PG 2 is H or an amino protecting group, preferably t-butoxycarbonyl (Boc);
  • R a and R a ' are each independently selected from H and C 1-6 alkyl at each occurrence; or R a and R a ' together with the group to which they are attached form a 5-10 membered ring system;
  • reaction conditions of each step are as follows:
  • the first step reacting compound a-1 with boric acid or boric acid ester under the catalysis of a palladium catalyst, preferably in the presence of a base, to obtain compound b-1;
  • Second step reacting compound b-1 with compound REG-1 under the catalysis of a palladium catalyst, preferably in the presence of a base, to give compound c-1;
  • Step 3 reacting compound c-1 with compound REG-2 (preferably in the presence of a suitable condensing agent and a suitable base) to provide a compound of formula (II);
  • the method comprises the steps of:
  • reaction conditions of each step are as follows:
  • First step reacting compound a-2 with compound REG-2 (preferably in the presence of a suitable condensing agent and a suitable base) to give compound b-2;
  • Second step reacting compound b-2 with boric acid or a boric acid ester under the catalysis of a palladium catalyst, preferably in the presence of a base, to give compound c-2;
  • the third step reacting compound c-2 with compound REG-1 under the catalysis of a palladium catalyst, preferably in the presence of a base, to obtain a compound of formula (II);
  • the method comprises the steps of:
  • reaction conditions of each step are as follows:
  • the first step reacting compound a-1 with boric acid or boric acid ester under the catalysis of a palladium catalyst, preferably in the presence of a base, to obtain compound b-1;
  • the second step deprotecting compound b-1 under the conditions corresponding to PG 1 , to obtain compound c-3;
  • Step 3 reacting compound c-3 with compound REG-2 (preferably in the presence of a suitable condensing agent and a suitable base) to give compound d-3;
  • the invention provides a method of preparing a compound of formula (XII), comprising the steps of:
  • R 2 is H
  • Hal 1 and Hal 2 are the same or different halogens, such as F, Cl, Br or I;
  • PG 1 is a carboxy protecting group, preferably a C 1-6 alkyl group
  • PG 2 is H or an amino protecting group, preferably t-butoxycarbonyl (Boc);
  • R a and R a ' are each independently selected from H and C 1-6 alkyl at each occurrence; or R a and R a ' together with the group to which they are attached form a 5-10 membered ring system;
  • reaction conditions of each step are as follows:
  • the first step reacting compound a-1 with boric acid or boric acid ester under the catalysis of a palladium catalyst, preferably in the presence of a base, to obtain compound b-1;
  • Second step reacting compound b-1 with compound REG-1' under the catalysis of a palladium catalyst, preferably in the presence of a base, to give compound c-1';
  • the third step reacting compound c-1' with compound REG-2' (preferably in the presence of a suitable condensing agent and a suitable base) to give a compound of formula (XII).
  • the invention provides a method of preparing a compound of formula (XIII), comprising the steps of:
  • R 2 is H
  • Hal 1 and Hal 2 are the same or different halogens, such as F, Cl, Br or I;
  • PG 1 is a carboxy protecting group, preferably a C 1-6 alkyl group
  • PG 2 is H or an amino protecting group, preferably t-butoxycarbonyl (Boc);
  • R a and R a ' are each independently selected from H and C 1-6 alkyl at each occurrence; or R a and R a ' together with the group to which they are attached form a 5-10 membered ring system;
  • reaction conditions of each step are as follows:
  • the first step reacting compound a-1 with boric acid or boric acid ester under the catalysis of a palladium catalyst, preferably in the presence of a base, to obtain compound b-1;
  • Second step reacting compound b-1 with compound REG-1 under the catalysis of a palladium catalyst, preferably in the presence of a base, to give compound c-1;
  • the third step reacting compound c-1 with compound REG-2' (preferably in the presence of a suitable condensing agent and a suitable base) to give a compound of formula (XIII).
  • the invention provides a method of preparing a compound of formula (XIV), comprising the steps of:
  • R 2 is H
  • Hal 1 and Hal 2 are the same or different halogens, such as F, Cl, Br or I;
  • PG 1 is a carboxy protecting group, preferably a C 1-6 alkyl group
  • PG 2 is H or an amino protecting group, preferably t-butoxycarbonyl (Boc);
  • R a and R a ' are each independently selected from H and C 1-6 alkyl at each occurrence; or R a and R a ' together with the group to which they are attached form a 5-10 membered ring system;
  • reaction conditions of each step are as follows:
  • the first step reacting compound a-1 with boric acid or boric acid ester under the catalysis of a palladium catalyst, preferably in the presence of a base, to obtain compound b-1;
  • Second step reacting compound b-1 with compound REG-1' under the catalysis of a palladium catalyst, preferably in the presence of a base, to give compound c-1';
  • Third step reacting compound c-1' with compound REG-2 (preferably in the presence of a suitable condensing agent and a suitable base) to provide a compound of formula (XIV);
  • the method comprises the steps of:
  • reaction conditions of each step are as follows:
  • First step reacting compound a-2 with compound REG-2 (preferably in the presence of a suitable condensing agent and a suitable base) to give compound b-2;
  • Second step reacting compound b-2 with boric acid or a boric acid ester under the catalysis of a palladium catalyst, preferably in the presence of a base, to give compound c-2;
  • the method comprises the steps of:
  • reaction conditions of each step are as follows:
  • the first step reacting compound a-1 with boric acid or boric acid ester under the catalysis of a palladium catalyst, preferably in the presence of a base, to obtain compound b-1;
  • the second step deprotecting compound b-1 under the conditions corresponding to PG 1 , to obtain compound c-3;
  • Step 3 reacting compound c-3 with compound REG-2 (preferably in the presence of a suitable condensing agent and a suitable base) to give compound d-3;
  • the boric acid or borate ester is, for example, a bis pinacol borate.
  • the palladium catalyst is, for example, Pd(dppf)Cl 2 , Pd(PPh 3 ) 4 , Pd(OAc) 2 or Pd(PPh 3 ) 2 Cl 2 .
  • the condensing agent is, for example, DCC, EDCI, HATU, PyBOP.
  • the suitable base is, for example, diisopropylethylamine, triethylamine, pyridine, sodium carbonate, potassium acetate, potassium carbonate, potassium hydroxide, cesium carbonate.
  • compositions and methods of treatment are provided.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate thereof, An N-oxide, an isotopically-labeled compound, a metabolite or prodrug, and one or more pharmaceutically acceptable carriers, preferably a solid formulation, a semi-solid formulation, a liquid formulation or a gaseous formulation.
  • the pharmaceutical composition may further comprise one or more additional therapeutic agents.
  • the invention provides a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite thereof Or the use of a prodrug or a pharmaceutical composition of the invention in the manufacture of a medicament for use as a Rho-related protein kinase (ROCK) inhibitor, preferably a selective ROCK2 inhibitor.
  • a Rho-related protein kinase (ROCK) inhibitor preferably a selective ROCK2 inhibitor.
  • the invention provides a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite thereof Or a prodrug or a pharmaceutical composition of the invention for use as a Rho-associated protein kinase (ROCK) inhibitor, preferably a selective ROCK2 inhibitor.
  • a Rho-associated protein kinase (ROCK) inhibitor preferably a selective ROCK2 inhibitor.
  • the invention provides a method of preventing or treating a Rho-associated protein kinase (ROCK) mediated disease, the method comprising administering to a subject in need thereof an effective amount of a compound of the invention or a pharmaceutically acceptable compound thereof Salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs or pharmaceutical compositions of the invention.
  • a Rho-associated protein kinase mediated disease
  • the Rho-related protein kinase (ROCK) mediated diseases include autoimmune diseases (including rheumatoid arthritis, systemic lupus erythematosus (SLE; lupus), psoriasis, Crohn Disease, atopic dermatitis, eczema or graft-versus-host disease (GVHD); cardiovascular disease (including hypertension, atherosclerosis, restenosis, cardiac hypertrophy, cerebral ischemia, cerebral vasospasm or erectile dysfunction) ) inflammation (including asthma, cardiovascular inflammation, ulcerative colitis or kidney inflammation); central nervous system disease Symptom (which includes neuronal degeneration or spinal cord injury; the central nervous system disorder is preferably Huntington's disease, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS) or multiple Sclerosis); arterial thrombotic disorder (which includes platelet aggregation or leukocyte aggregation); fibrotic disorder (which includes liver fibrosis
  • the Rho-associated protein kinase (ROCK) mediated diseases include lupus nephritis, atherosclerosis, rheumatoid arthritis (RA), hemangioma, angiofibroma, pulmonary fibrosis, psoriasis Disease, corneal transplant rejection, insulin-dependent diabetes mellitus, multiple sclerosis, myasthenia gravis, Crohn's disease, autoimmune nephritis, primary biliary cirrhosis, acute pancreatitis, allogeneic rejection, allergic inflammation, Contact dermatitis, delayed hypersensitivity, inflammatory bowel disease, septic shock, osteoporosis, osteoarthritis, neuronal inflammation, Osler-Weber syndrome, restenosis, fungal infection, parasitic infection, and viral infection.
  • RA rheumatoid arthritis
  • hemangioma angiofibroma
  • pulmonary fibrosis psoriasis Disease
  • “Pharmaceutically acceptable carrier” in the context of the present invention means a diluent, adjuvant, excipient or vehicle with which the therapeutic agent is administered, and which is suitable for contacting humans and/or within the scope of sound medical judgment. Tissues of other animals without excessive toxicity, irritation, allergic reactions, or other problems or complications corresponding to a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, sterile liquids such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, minerals. Oil, sesame oil, etc. Water is an exemplary carrier when the pharmaceutical composition is administered intravenously. It is also possible to use physiological saline and an aqueous solution of glucose and glycerin as a liquid carrier, particularly for injection.
  • Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skimmed milk powder, glycerin, propylene glycol, water, Ethanol and the like.
  • the composition may also contain minor amounts of wetting agents, emulsifying agents or pH buffering agents as needed.
  • Oral formulations may contain standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like. Examples of suitable pharmaceutically acceptable carriers are as described in Remington's Pharmaceutical Sciences (1990).
  • compositions of the invention may act systemically and/or locally.
  • they may be administered in a suitable route, for example by injection (for example intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular, including instillation) or transdermal administration; or by oral, buccal, or oral administration.
  • injection for example intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular, including instillation
  • transdermal administration or by oral, buccal, or oral administration.
  • compositions of the invention may be administered in a suitable dosage form.
  • the dosage forms include, but are not limited to, tablets, capsules, troches, hard candy, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, aqueous suspensions. Injectable solutions, elixirs, syrups.
  • an effective amount refers to an amount of a compound that, to a certain extent, relieves one or more symptoms of the condition being treated after administration.
  • the dosing regimen can be adjusted to provide the optimal desired response. For example, a single bolus may be administered, several divided doses may be administered over time, or the dose may be proportionally reduced or increased as indicated by the urgent need for treatment. It is noted that the dose value can vary with the type and severity of the condition to be alleviated and can include single or multiple doses. It is to be further understood that for any particular individual, the particular dosage regimen will be adjusted over time according to the individual needs and the professional judgment of the person administering the composition or the composition of the supervised composition.
  • an effective dose will be from about 0.0001 to about 50 mg per kg body weight per day, for example from about 0.01 to about 10 mg/kg/day (single or divided doses). For a 70 kg person, this would add up to about 0.007 mg/day to about 3500 mg/day, such as from about 0.7 mg/day to about 700 mg/day.
  • a dose level that is not higher than the lower limit of the aforementioned range may be sufficient, while in other cases, a larger dose may still be employed without causing any harmful side effects, provided that the larger The dose is divided into several smaller doses to be administered throughout the day.
  • the amount or amount of the compound of the present invention in the pharmaceutical composition may be from about 0.01 mg to about 1000 mg, suitably from 0.1 to 500 mg, preferably from 0.5 to 300 mg, more preferably from 1 to 150 mg, particularly preferably from 1 to 50 mg, for example, 1.5 mg, 2 mg, 4 mg, 10 mg, 25 mg, and the like.
  • treating means reversing, alleviating, inhibiting the progression of a condition or condition to which such a term applies or one or more symptoms of such a condition or condition, or Prevent such illness or condition or this One or more symptoms of a condition or condition.
  • “Individual” as used herein includes human or non-human animals.
  • Exemplary human individuals include a human individual (referred to as a patient) or a normal individual having a disease, such as the disease described herein.
  • “Non-human animals” in the present invention include all vertebrates, such as non-mammals (eg, birds, amphibians, reptiles) and mammals, such as non-human primates, domestic animals, and/or domesticated animals (eg, sheep, dogs). , cats, cows, pigs, etc.).
  • compositions of the invention may also comprise one or more additional therapeutic or prophylactic agents.
  • the structure of the compound was confirmed by nuclear magnetic resonance spectroscopy ( 1 H NMR) or mass spectrometry (MS).
  • the chemical shift ( ⁇ ) is given in parts per million (ppm).
  • the 1 H NMR measurement was carried out on a Bruker BioSpin GmbH 400 nuclear magnetic instrument.
  • the test solvent was deuterated methanol (CD 3 OD), deuterated chloroform (CDCl 3 ) or hexamethyl dimethyl sulfoxide (DMSO-d 6 ). Marked as tetramethylsilane (TMS).
  • the LC-MS was measured on a Shimadzu LC-MS-2020 LC/MS (manufacturer: Shimadzu, model: Shimadzu LC-MS-2020).
  • Thin layer chromatography was carried out using a yellow sea brand HSGF 254 (5 ⁇ 20 cm) silica gel plate, and thin layer preparative chromatography was carried out using a silica gel plate of GF 254 (0.4-0.5 nm) manufactured by Yantai.
  • the reaction is detected by thin layer chromatography (TLC) or LC-MS using a developing solvent system including a dichloromethane and methanol system, a n-hexane and ethyl acetate system, and a petroleum ether and ethyl acetate system depending on the compound to be separated.
  • the developing agent system is adjusted by the difference in polarity (by adjusting the volume ratio of the solvent or adding triethylamine or the like).
  • the microwave reaction was carried out using a Biotage Initiator + (400 W, RT ⁇ 300 ° C) microwave reactor.
  • Column chromatography is generally used in the chemical industry 200 ⁇ 300 mesh silica gel as a stationary phase.
  • the system of the eluent includes a dichloromethane and methanol system and a n-hexane and ethyl acetate system, and the eluent system is adjusted according to the polarity of the compound to be separated (by adjusting the volume ratio of the solvent or adding triethylamine, etc.) get on).
  • the temperature of the reaction is room temperature (20 ° C to 30 ° C) as otherwise specified in the examples.
  • the reagents used in the examples were purchased from companies such as Acros Organics, Aldrich Chemical Company or Shanghai Bied Pharmaceutical Technology Co., Ltd.
  • TDI01314-1-a (8.00 g, 37.20 mmol) and 2-(chloromethyl)oxirane (6.88 g, 74.40 mmol) were dissolved in acetonitrile (200 mL) and potassium carbonate (15.42 g, 111.60 mmol) And reacted at 80 ° C overnight. Thin layer chromatography showed complete reaction. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjj MS m/z (ESI): 271.1;
  • TDI01314-1-b (6 g, 22.13 mmol) was dissolved in dichloromethane (100 mL), and m-chloroperoxybenzoic acid (7.64 g, 44.26 mmol) was added and reacted at 40 ° C for 8 hours. Thin layer chromatography showed complete reaction. The reaction solution was cooled to room temperature, and a saturated sodium sulfite solution was added and stirred for half an hour. A white solid was precipitated, filtered, and the organic phase was concentrated, and then the crude material was purified by column chromatography to afford TDI01314-1-c (3 g, white solid, yield: 47.21%). MS m/z (ESI): 287.1; 289.1 [M+H].
  • TDI01314-1-c (3 g, 10.45 mmol) was dissolved in tetrahydrofuran (100 mL) and water (10 mL), and sodium hydroxide (835.85 mg, 20.90 mmol) was added and allowed to react overnight at room temperature. Thin layer chromatography showed complete reaction. The reaction mixture was extracted with EtOAc. EtOAc EtOAc.
  • TDI01314-1-d (2 g, 8.16 mmol) was added to water (100 mL), and then potassium carbonate (2.26 g, 16.32 mmol) and potassium permanganate (2.58 g, 16.32 mmol) were added and reacted at room temperature for 12 hours. LC-MS detection showed complete reaction. The reaction mixture was filtered, and the filtrate was evaporated to ethylamine.
  • Preparation of intermediate TDI01212-a refers to the first and second steps of Example 1, and will be in the first step use instead.
  • the intermediate TDI01212-a (3.00 g, 9.97 mmol) was dissolved in a mixture of methanol and water (2:1) (60 mL), and lithium hydroxide monohydrate (4.19 g, 99.7 mmol) was added. The reaction was overnight. LC-MS showed the reaction was complete. The reaction solution was concentrated under reduced pressure to remove methanol, and the aqueous phase was adjusted to pH 3 with 6N HCl. A large solid was precipitated and stirred at room temperature for 30 minutes, and filtered to give intermediate TDI01212-b (2.1 g, yellow solid, yield: 73.2%) .
  • reaction solution was concentrated under reduced pressure, the pH was adjusted to 3-4, and filtered to give a solid, 1.5 g, and then 20 mL of MTBE was obtained to obtain a mixture. After drying, compound TDI01212-3 (0.4 g, yellow solid, yield: 27%) was obtained.
  • the first step is a first step:
  • Trifluoroacetic acid (1 mL) was added to a solution of TDI01160-4 (30 mg, 0.055 mmol) in dichloromethane (3 mL). LC-MS showed the reaction was complete. The reaction solution was cooled to room temperature, and then evaporated, evaporated, evaporated,,,,,,,,,,,,,
  • the compound TDI01229-1 (3 g, 15.3 mmol) was dissolved in anhydrous acetonitrile (100 mL), acetyl chloride (9.69 g, 61.2 mmol) and cesium carbonate (19.95 g, 61.2 mmol) were added, and the reaction mixture was reacted at 50 ° C. hour. LC-MS monitoring showed complete reaction.
  • the reaction solution was cooled to room temperature, filtered, evaporated, evaporated, evaporated, crystals crystalssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssss
  • reaction mixture was concentrated under reduced pressure to drynessnessnessnessnessnessssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssss
  • TDI01147-3 (570 mg, 2.07 mmol) was dissolved in ethanol (12 mL), hydrazine hydrate (3 mL) was added, and the mixture was reacted at 90 ° C for 1 hour. LC-MS showed half of the starting material and product. The reaction mixture was diluted with EtOAc (EtOAc) (EtOAc)EtOAc. TDI01147-4 (300 mg, yellow solid, yield: 52.6%).
  • the compound TDI01234-1 (2.0 g, 8.86 mmol) was dissolved in 1,2-dichloroethane (150 mL), triethylamine (746 mg, 7.38 mmol) was added, and the reaction mixture was warmed to 30 ° C and stirred for 1.5 hours. Then, 5-amino-1H-carbazole-1-carboxylic acid tert-butyl ester (1.72 g, 7.38 mmol) and acetic acid (443 mg, 7.38 mmol) were added, and stirred for 0.5 hour, then sodium triacetoxyborohydride (4.69 g, 22.14) was added. Mm), keep The reaction was carried out at 30 ° C overnight.
  • the compound TDI01234-2 (0.6 g, 1.478 mmol) was dissolved in methanol (50 mL), palladium/carbon (100 mg) was added, and the mixture was replaced with hydrogen three times and placed in a 35 ° C oil bath overnight. LC-MS showed the reaction was complete. The reaction solution was cooled to room temperature, filtered, evaporated, evaporated, evaporated, evaporated,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,
  • reaction solution was diluted with water (80 mL), ethyl acetate (100 mL*2), and the organic phase was combined and washed successively with 0.5 M HCl (80 mL*2) and saturated brine (100 mL*2) Dry, filter and concentrate to give compound TDI01247-2 (2.8 g, yellow solid, yield: 70%).
  • Phenyl chloroformate (1.24 g, 7.89 mmol) was added to a solution of TDI01237-1 (500 mg, 5.27 mmol) and triethylamine (1.06 g, 10.54 mmol) in dichloromethane (10 mL) Reaction 2h. The reaction was monitored by LC-MS. It was quenched with water (15 mL), EtOAc (EtOAc)EtOAc. MS m/z (ESI): 216.1 [M+H].
  • reaction solution was cooled to room temperature, and then evaporated, evaporated, evaporated, mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj
  • Trifluoroacetic acid (1 mL) was added to a solution of TDI01237-5 (30 mg, 0.055 mmol) in dichloromethane (3 mL). LC-MS showed the reaction was complete. The reaction solution was cooled to room temperature, then evaporated, evaporated, evaporated, evaporated,
  • TDI01239-1 500 mg, 2.358 mmol was dissolved in tetrahydrofuran (24 mL) and cooled to 0 ° C.
  • 60% NaH (236 mg, 5.895 mmol) was added to the above reaction mixture under nitrogen atmosphere, and the mixture was reacted at room temperature for 1 h.
  • ethyl bromoacetate was added at 0 ° C, followed by a reaction at room temperature for 2 h.
  • the reaction was completed by LC-MS. After the completion of the reaction, the reaction mixture was combined with EtOAc (EtOAc) (EtOAc) 2 (700 mg, yellow solid, yield: 99.57%).
  • TDI01239-2 700 mg, 2.357 mmol
  • lithium hydroxide monohydrate 297 mg, 7.071 mmol
  • TDI01239-3 0.3 g, 1.115 mmol
  • bispinacol borate 425 mg, 1.673 mmol
  • potassium acetate 328 mg, 3.345 mmol
  • Pd(dppf)Cl 2 82 mg, 0.1115 mmol
  • TDI01239-4 350mg, 1.104mmol
  • Reg-1-1 254mg, 0.736mmol
  • sodium carbonate (234mg, 2.208mmol)
  • Pd (PPh 3 ) 2 Cl 2 52 mg, 0.0736 mmol
  • the reaction was completed by LC-MS. EtOAc was evaporated. , yield: 29.48%).
  • TDI01239-5 70mg, 0.175mmol
  • 4-aminopyridazine 20mg, 0.21mmol
  • HATU 66mg, 0.175mmol
  • diisopropyl Ethylethylamine 68 mg, 0.525 mmol
  • the obtained solid was purified by high-performance liquid chromatography to yield Compound TDI01239 (5.29 mg,yield:yield: 6.37%).
  • TDI01272-2 (5.20 g, 23.6 mmol) was dissolved in dichloromethane (150 mL), triethylamine (7.15 g, 70.8 mmol) was added, and methanesulfonyl chloride (4.04 g, 35.5 mmol) was added in an ice bath. The reaction was carried out for 3 h at room temperature. Thin layer chromatography showed complete reaction. The reaction was quenched with EtOAc EtOAc (EtOAc)EtOAc. g, yellow oil, crude).
  • TDI01272-6 300 mg, 0.96 mmol
  • paraformaldehyde 144 mg, 4.81 mmol
  • 1,2-dichloroethane 10 mL
  • 5 drops of acetic acid were added, and stirred at room temperature for 1 hour, then NaBH (OAc) was added.
  • 3 611 mg, 2.88 mmol
  • the reaction solution was allowed to react at room temperature overnight.
  • the reaction mixture was quenched with EtOAc EtOAc (EtOAc)EtOAc.
  • EtOAc EtOAc
  • TDI01272-7 (98.8 mg, 0.303 mmol) and Reg-1-2 (100 mg, 0.253 mmol) were dissolved in a mixture of ethanol:water (8:1) (9 mL), and sodium carbonate (53.6 mg, 0.506 mmol) was added. And Pd(PPh 3 )Cl 2 (17.6 mg, 0.025 mmol), argon gas was replaced 3 times, and microwave (110 ° C) was reacted for 1 hour. LC-MS showed the reaction was complete.
  • reaction solution was cooled to room temperature, and then evaporated, evaporated, evaporated, evaporated, evaporated,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,
  • the first step is a first step:
  • Trifluoroacetic acid (1 mL) was added to a solution of TDI01287-4 (50 mg, 0.1 mmol) in dichloromethane (3 mL). LC-MS detection showed complete reaction. The reaction mixture was cooled to room temperature, then evaporated, evaporated, evaporated, evaporated,
  • TDI01288-3 300 mg, 1.159 mmol
  • Reg-1-1 200 mg, 0.579 mmol
  • ethanol 8 ml
  • water 1 ml
  • sodium carbonate 184 mg, 1.737 mmol
  • Pd ( PPh 3 ) 2 Cl 2 41 mg, 0.0579 mmol
  • TDI01298-1 (6 g, 27.27 mmol), methyl 3-aminopropionate (3.8 g, 27.27 mmol), potassium carbonate (11.29 g, 81.81 mmol) and 60 mL of tetrahydrofuran were added to a 100 mL sealed tube. The temperature was raised to 100 ° C and reacted for 5 h, and LC-MS showed the reaction was completed. The reaction solution was filtered, and the filtrate was evaporated. mjjjjjj MS m/z (ESI): 305.1 [M+H].
  • TDI01298-2 (8.5 g, 28 mmol), zinc powder (18.2 g, 280 mmol), ammonium chloride (15 g, 280 mmol) and 260 mL of methanol were added to a 500 mL flask, and the mixture was heated to 50 ° C for 2 h. LC-MS showed complete reaction. . The reaction solution was filtered, and the filtrate was collected. The filtrate was concentrated to dry oil to purified crystals eluted eluted elution : 70.7%).
  • TDI01298-4 (4 g, 15.44 mmol), HATU (7.06 g, 18.53 mmol), diisopropylethylamine (8.0 g, 61.8 mmol) and 150 mL of N,N-dimethylformamide were added to a 250 mL flask. The reaction was allowed to proceed for 0.5 h at room temperature, and LC-MS showed the reaction was completed. The reaction mixture was combined and evaporated to EtOAc EtOAc EtOAc EtOAc (EtOAc) g, brown solid, yield: 100%).
  • TDI01311-1 (2.4g, 10mmol) and thionyl chloride (10mL) were added to the 25mL flask, and 1 drop of dry N,N-dimethylformamide was carefully added dropwise with stirring, and the oil bath was heated to 70 °C. , reaction 1h. After the reaction solution became clear, thionyl chloride was removed under reduced pressure. The residue was dissolved in dichloromethane (10 mL).
  • 2-Aminopyridine (1.13 g, 12 mmol), diisopropylethylamine (3.88 g, 30 mmol), and dichloromethane (10 mL) were sequentially added to a 50 mL three-necked flask, and the mixture was replaced with nitrogen three times. Under ice-cooling and nitrogen atmosphere, a dichloromethane solution (10 mL) of the product obtained in one step was carefully added dropwise. After the addition was completed, the mixture was stirred at 0 ° C for 15 minutes, then the ice bath was removed, and the reaction was carried out at room temperature for 2 hours. LC-MS showed the reaction was completed.
  • TDI01311-3 800 mg, 2.53 mmol
  • bispinacol borate 964 mg, 3.80 mmol
  • potassium acetate 496 mg, 5.06 mmol
  • dioxane 20 mL
  • 1 drop 1 drop was added to a 100 mL flask.
  • Thionyl chloride was replaced three times with nitrogen.
  • Pd(dppf)Cl 2 185 mg, 0.253 mmol was carefully added, and after the addition was completed, the oil was reacted at 120 ° C for 2 hours.
  • TDI01311-4 200 mg, 0.449 mmol
  • Reg-1-27 196 mg, 0.539 mmol
  • potassium phosphate 190 mg, 0.898 mmol
  • tetrahydrofuran 3 mL
  • water 0.5 mL
  • TDI01311-5 (20 mg, 0.03 mmol) and dichloromethane (1 mL) were added to a 10 mL flask, and trifluoroacetic acid (1 mL) was added dropwise with stirring, and the mixture was stirred at room temperature for 1 hour. LC-MS detection showed the reaction was completed, and the solvent was removed under reduced pressure to give compound TDI 01311 (7.24 mg,yield:yield: 41.9%).
  • TDI01312-1 150 mg, 1.765 mmol
  • 5-bromoisoindoline 620 mg, 2.647 mmol
  • diisopropylethylamine 341 mg, 2.647 mmol
  • dichloromethane 9 mL
  • TDI01312-2 300 mg, 1.064 mmol
  • bis-pinacol borate 405 mg, 1.596 mmol
  • dioxane 10 mL
  • potassium acetate 312 mg, 3.192 mmol
  • Pd dppf
  • TDI01271-1 (1.0 g, 16.95 mmol) was dissolved in anhydrous dichloromethane (20 mL) and triethylamine (1.88 g, 18.64 mmol) and chloroacetyl chloride (2.1 g, 18.64 mmol). The reaction solution was reacted at room temperature for 5 hours. LC-MS detection showed complete reaction. The reaction mixture was concentrated with EtOAc EtOAc (EtOAc m. ).
  • TDI01271-2 400 mg, 2.96 mmol
  • 5-bromoisoindoline hydrochloride 696.3 mg, 2.96 mmol
  • the reaction solution was reacted at 90 ° C overnight.
  • LC-MS detection showed complete reaction.
  • the reaction mixture was concentrated with EtOAc EtOAc (EtOAc m. ).
  • TDI01271-3 400 mg, 1.347 mmol
  • bis-pinacol borate (648 mg, 2.694 mmol) were dissolved in 1,4-dioxane (20 mL), potassium acetate (528 mg, 5.388 mmol) and Pd(dppf)Cl 2 (98 mg, 0.1347 mmol) was replaced with argon three times and placed in an oil bath at 80 ° C overnight.
  • LC-MS detection showed complete reaction. The reaction solution was cooled to room temperature, and then evaporated, evaporated, evaporated,363363363363363363363363363363363363363363363363363363363363363363363363363363363363363363363363363363363363363363363363363363363363363363363363363363363363363363363363363363363363363363363363363363363363363363363363363363
  • TDI01286-1 (1.0 g, 16.95 mmol) was dissolved in anhydrous dichloromethane (20 mL) and triethylamine (1.88 g, 18.64 mmol) and chloroacetyl chloride (2.1 g, 18.64 mmol). The reaction solution was reacted at room temperature for 5 hours. LC-MS detection showed complete reaction. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjjjjjjj Crude). MS m/z (ESI): 136.2 [M+H].
  • reaction solution was slowly added to 100 mL of water and stirred at room temperature for 30 min, a large amount of solid was precipitated, the solid mixture was filtered, and the filter cake was washed, and the filter cake was collected and dried to give TDI01286-3 (800 mg, crude).
  • TDI01286-3 500 mg, 1.695 mmol
  • bis-pinacol borate 861 mg, 3.390 mmol
  • potassium acetate 664.4 mg, 6.780 mmol
  • Pd (dppf) Cl 2 124 mg, 0.1695 mmol
  • Thin layer chromatography showed complete reaction.
  • the reaction solution was cooled to room temperature, and then evaporated, evaporated, evaporated,3633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633
  • TDI01326-2 (2.6 g, 13.2 mmol) was dissolved in N,N-dimethylformamide (100 mL), EtOAc (5. After stirring for 30 minutes, 2-(4-methylpiperazin-1-yl)acetic acid (1.74 g, 11 mmol) was added, and the mixture was reacted at room temperature for 2 hours. LC-MS detection showed complete reaction. The reaction mixture was taken-up ⁇ Oily).
  • TDI01326-3 (3.0 g, 8.90 mmol) and bispinacol borate (3.4 g, 13.35 mmol) were dissolved in dioxane (100 mL), potassium acetate (2.62 g, 26.7 mmol) and Pd. (dppf)Cl 2 (312 mg, 0.45 mmol) was replaced with argon three times and placed in an oil bath at 80 ° C overnight. Thin layer chromatography showed complete reaction. The reaction solution was cooled to room temperature, then evaporated, evaporated, mjjjjjj
  • TDI01264-1 (3.0 g, 1.38 mmol) and 1,3-dibromopropane (8.35 g, 4.14 mmol) were dissolved in acetonitrile (100 mL), and potassium carbonate (6.09 g, 4.14 mmol) was added and the oil was placed at 80 ° C The reaction in the bath was carried out for 12 h. LC-MS detection showed complete reaction. The reaction mixture was cooled to room temperature, filtered, evaporated, evaporated, evaporated, evaporated, evaporated,
  • TDI01264-3 (0.7 g, 2.27 mmol) was dissolved in acetonitrile (100 mL), and potassium carbonate (0.626 g, 4.53 mmol) was added and the mixture was placed in an oil bath at 80 ° C for 12 h. LC-MS detection showed complete reaction. The reaction solution was cooled to room temperature, filtered, evaporated, evaporated, mjjjjjj
  • TDI01264-4 (0.27 g, 1.18 mmol) and bispinacol borate (0.599 g, 2.36 mmol) were dissolved in dioxane (30 mL), potassium acetate (0.347 g, 3.54 mmol) and Pd (dppf)Cl 2 (48 mg, 0.059 mmol), was replaced with argon three times, and placed in an oil bath at 80 ° C for 12 h. LC-MS detection showed complete reaction. The reaction solution was cooled to room temperature, and then evaporated, evaporated, evaporated,3633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633633
  • TDI01264-5 160 mg, 0.581 mmol
  • Reg-1-27 (0.20 g, 0.465 mmol) were dissolved in a mixture of ethanol/water (10:1) (11 mL), and sodium carbonate (0.18 g, 11.74 mmol) was added.
  • Pd(PPh 3 ) 2 Cl 2 (20.39 mg, 0.029 mmol)
  • argon gas was exchanged for 3 times, and placed in a microwave at 110 ° C for 2 h.
  • LC-MS detection showed complete reaction.
  • the reaction solution was cooled to room temperature, filtered, and evaporated, evaporated,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,
  • HTRF KinEASE-STK S2 kit HTRF KinEASE-STK S2 kit (62ST2PEC) for 50 kinase assay IC.
  • the kinase ROCK2 (01-119) used in the reaction was purchased from Carna Biosciences.
  • the following working solutions were prepared with the corresponding reagents: 1 ⁇ kinase buffer, 5 ⁇ STK-S2 substrate working solution (1.5 ⁇ M) and 5 ⁇ ATP working solution (1.5 ⁇ M). 5 ⁇ ROCK2 kinase working solution, 4 ⁇ streptavidin-XL665 working solution, 4 ⁇ STK-Ab-cryptate 2 detection solution, and then the following operation.
  • a 10000 nM compound solution was prepared by using a DMSO concentration of 2.5% in 1 ⁇ kinase buffer, and the compound was further diluted with the above DMSO-containing kinase buffer to obtain 9 different concentrations of the test compound solution.
  • positive wells containing all reagents except the compound
  • negative wells containing all reagents except the test compound and kinase
  • 4 ⁇ L of the test compound solution was added to all wells, and 4 ⁇ L of a 2.5% DMSO solution was added to the control wells.
  • 2 ⁇ M of substrate i.e., 2 ⁇ L of 5 ⁇ STK-S2 substrate working solution
  • 2 ⁇ M of substrate i.e., 2 ⁇ L of 5 ⁇ STK-S2 substrate working solution
  • 2 ⁇ L of 5 ⁇ ROCK2 kinase working solution containing 1.4 ng of ROCK2 kinase
  • the negative wells were made up with 2 ⁇ L of 1 ⁇ kinase buffer.
  • 2 ⁇ L of 5 ⁇ ATP working solution was added to all wells and incubated for 2 hours at room temperature.
  • IC 50 values of the compounds are shown in the table below.
  • TDI01136 66 TDI01140 109 TDI01141 73 TDI01142 225 TDI01143 72 TDI01149 100 TDI01151 45 TDI01152 88 TDI01153 16 TDI01156 25 TDI01160 54 TDI01161 210 TDI01164 438 TDI01167 223 TDI01171 63 TDI01175 197 TDI01176 28 TDI01177 71 TDI01178 168 TDI01180 37 TDI01181 92 TDI01182 46 TDI01188 123 TDI01191 225 TDI01199 30 TDI01200 twenty three TDI01201 48 TDI01213 255 TDI01215 382 TDI01221 91 TDI01230 109 TDI01232 295 TDI01236 135 TDI01237 171 TDI01247 134 TDI01250 208
  • TDI01318 18 TDI01320 410 TDI01324 101 TDI01327 472 TDI01330 474 TDI01331 260 TDI01332 257 TDI01337 121 TDI01338 115 TDI01339 147 TDI01343 436 TDI01344 97 TDI01345 333 TDI01347 356 TDI01354 254 TDI01355 54 TDI01363 104 TDI01366 260 TDI01369 266 TDI01370 109 TDI01379 411 TDI01381 341 TDI01393 258 TDI01397 120 TDI01398 16 TDI01344-2A 107 TDI01408 400 TDI01411 258 TDI01415 262 TDI01418 272 TDI01420 477 TDI01421 289 TDI01423

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